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1CHENODEOXYCHOLIC ACID (CDCA) AS A SIGNALING MOLECULE IN THE REGULATION OF METABOLIC PROCESSES Pavlova E.K.1, Yadav V.2
1Pavlova Evgeniya Konstantinovna - teacher, 2Yadav Vishal - student,
FEDERAL STATE BUDGETARY EDUCATIONAL INSTITUTION OF HIGHER EDUCATIONMARI STATE UNIVERSITY,
YOSHKAR-OLA
Abstract: chenodeoxycholic acid (CDCA) is an essential bile acid that acts as a signalling molecule in the human body. CDCA is able to regulate the activity of genes involved in immune response, inflammation and metabolic processes. CDCA plays a role in the regulation ofthe immune system by modulating the activity of immune cells such as macrophages and dendritic cells, influencing the recognition and response to pathogens. CDCA participates in the metabolism of fats and carbohydrates, is able to stimulate the synthesis of proteins involved in the synthesis of nuclear receptors, and allows to regulate the expression of genes responsible for metabolic processes in the body. The aim of this review is to analyse current research on the use of CDCA as a therapeutic agent, which is a discovery in the development of new methods for the treatment of diseases.
Keywords: bile acids, chenodeoxycholic acid (CDCA), farnesoid X receptor, liver X receptor, G protein-coupled bile acid receptor 1, human.
UDC 577.1
1. Biosynthesis and Regulation of Chenodeoxycholic acid
Bile acids (BA) are the end products of cholesterol metabolism, actively participating in the processes of digestion and absorption of fats, and are considered as transgenomic metabolites. Hepatocytes are the site of BA synthesis, where, under the action of cytochrome P450, cholesterol is oxidized in a complex multi-step process. The main pathway for BA synthesis begins with the hydroxylation of cholesterol at position 7a using CYP7A1 [1].
The next step involves oxidation of 3P-OH and isomerization of the C5-C6 double bond by microsomal C27-3P-hydroxysteroid dehydrogenase (C27-3P-HSD). The resulting intermediate is then either hydroxylated at the 12a position by microsomal CYP8B1 or passed directly to the next step. The 12a-OH intermediates and those that have not undergone 12a-hydroxylation are then subjected to reduction of the C4-C5 double bond by the enzyme oxosteroid 5p reductase. This is followed by reduction of the C3-oxo group by the enzyme 3a-HSD to yield 3a-OH intermediates [2]. The 12a-hydroxylated intermediates ultimately produce cholic acid (CA), while the intermediates that were not hydroxylated ultimately produce chenodeoxycholic acid (CDCA). CDCA and CA are the primary BAs in humans.
When CYP7A1 activity is deficient, minor pathways for bile acid synthesis are present, with CDCA being predominantly produced [3]. These pathways are initiated via the hydroxylation of the cholesterol side chain at the different positions (C24, C25, or C27) by various enzymes including, CYP46A1, cholesterol 25-hydroxylase, and CYP27A1. The resulting oxysterols are further hydroxylated at the 7a position by CYP7B1 or CYP3 9A1. These pathways are known as the "alternative" or "acidic" pathways of bile acid synthesis.
Following multi-step synthesis, CDCA combines with taurine or glycine to create bile salts, which are then released into bile and stored in the gallbladder. When food is consumed, bile salts are released into the small intestine, thereby aiding in the emulsification and absorption of fats. In the intestine, some CDCA is deconjugated and converted into secondary bile acids such as lithocholic acid (LCA) by intestinal microorganisms. CDCA and its derivatives are reabsorbed in the lower small intestine and transported back to the liver via the enterohepatic circulation, where they can be reused [4] (Fig. 1).
CDCA serves as a powerful signaling molecule, mainly by interacting with nuclear receptors and G-protein-coupled receptors. These interactions initiate and regulate multiple metabolic pathways that control lipid, glucose, and energy balance at the genetic level. This presents an opportunity to create novel treatments for diseases associated with these processes.
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Fig. 1. Synthesis pathways of CDCA in hepatocytes and secondary bile acids LCA, UDCA in intestine. CDCA in the regulation of glucose and lipid homeostasis. The relationship between CDCA and FXR, FGF19, TGR5 and GLP-1.
Note: MRP2- multidrug resistance-associated protein 2; BSEP- bile salt export pump; NTCP- sodium/taurocholate co-transporting polypeptide; FXR- Famesoid X receptor; OSTa- Organic Solute Transporter a; OSTP- Organic Solute Transporter P; ASBT- apical sodium-dependent bile acid transporter; FGFR4/KLB- fibroblast growth factor receptor/ coreceptor klotho b; FGF-15- fibroblast growth factor-15; CYP7A1- Cytochrome P450, Family 7, Subfamily A, Polypeptide 1; CYP8B1- Cytochrome P450, Family 8, Subfamily B, Polypeptide 1; CA- Cholic acid; CDCA-Chenodeoxycholic acid; T/G-CA/CDCA- Tauro/Glyco-Cholic acid/ Chenodeoxycholic acid; GLP-1- Glucagon-like peptide-1; LCA- Lithocholic acid; UDCA- Ursodeoxycholic acid; TGR5- Takeda G protein-coupled receptor; cAMP- Cyclic adenosine monophosphate; DIO2- deiodinase iodothyronine type II; T4- thyroxine; T3- triiodothyronine; SREBP1- sterol regulatory element-binding protein 1.
2 CDCA as a signaling molecule in metabolic reactions
2.1 CDCA - ligandfor Farnesoid receptors (FXRs)
Farnesoid receptors (FXRs) are nuclear receptors that are highly expressed in the liver and intestines. They act as transcription factors, regulating the activation of particular genes in reaction to ligands. One such ligand for FXR is CDCA, an endogenous substance. When CDCA binds to FXR, it causes conformational changes that activate the receptor. Natural bile acids (BAs) have varying potencies in activating FXR, with CDCA being the most potent, followed by DCA, LCA, and CA [5]. Once activated, FXR binds to DNA and regulates the expression of genes involved in the synthesis, transport, and detoxification of bile acids. This regulatory pathway is particularly important for hydrophobic BAs, such as CDCAs, as their hydrophobicity and conjugation state play a critical role in regulating intestinal cholesterol and lipid absorption [6]. Ablation of CYP8B1 prevents weight gain and hepatic steatosis caused by a western diet due to decreased fat absorption [7]. FXR activation inhibits CYP7A1 and CYP8B1, reducing bile acid synthesis and preventing accumulation and toxicity, while also inducing the expression of SHP, a tumor suppressor gene that represses genes involved in bile acid production. Disruption of bile acid homeostasis by FXR deficiency leads to inflammation, injury, and uncontrolled cell proliferation, ultimately resulting in liver tumorigenesis [8].
CDCA is essential for regulating lipid metabolism. When CDCA activates FXR, it lowers triglyceride levels by suppressing genes linked to lipogenesis, like SREBP-1c, and boosting genes responsible for fatty acid oxidation [9]. Research shows that substituting the carboxylic group on CDCA's side chain with a 6-alkyl group significantly enhances its FXR activation, aligning with the hydrophobic pocket in FXR that matches the 6 position [5].
CDCA possesses anti-inflammatory properties by activating FXR. FXR activation suppresses the NF-kB signaling pathway, leading to decreased expression of pro-inflammatory cytokines and promoting better liver and intestinal health. This anti-inflammatory action of CDCA may be helpful in treating conditions like NAFLD and IBD [10].
2.2 Mechanism of TGR5 activation under the action of CDCA
CDCA also activates the G protein-coupled bile acid receptors (GPBAR1 or TGR5), which is found in various tissues such as the intestines, liver, and adipose tissue. CDCA acts as a natural ligand for this G protein-coupled receptor. In vitro research has shown that activation of TGR5 leads to signal transduction through Gs protein-mediated cAMP accumulation [11].
Data analysis indicates that CDCA, even at low doses, stimulates cyclin D1 protein expression via binding to the G protein-coupled receptor 5 (TGR5) in human endometrial adenocarcinoma (Ishikawa) cells. This leads to rapid cell
growth.Induction of cyclin D1 by CDCA involves enhanced recruitment of the transcription factor CREB to the cyclic AMP-responsive element motif in the proximal promoter of the cyclin D1 gene [12].
Other studies indicate that CDCA can induce the release of ATP from the cell membrane both through ion transport channels and by exocytosis. In turn, released ATP activates trimeric P2X receptors and G-protein coupled P2Y receptors, resulting in calcium influx either directly through P2XR or through G-protein coupled P2YR signaling, which can release calcium from intracellular stores and promote calcium influx. In addition, the poorly understood mechanism of TGR5 receptor activation by CDCA leads to an increase in calcium ion levels by stimulating adenylate cyclase and cAMP production. The Na+/Ca2+ exchanger (NCX) can be activated by TGR5, leading to calcium transport out of the cell or into the cell depending on the prevailing electrochemical gradients [13].
The TGR5 receptor under the influence of CDCA affects an increase in energy expenditure by enhancing the activation of thyroid hormones of the thyroid gland, as a result of which glucagon-like peptide-1 is released, which leads to insulin secretion. This suggests that it may be possible to control type 2 diabetes mellitus by activating TGR5 to regulate glucose balance. The effect of TGR on the cAMP-dependent enzyme that activates selenoproteins, namely deionidase type 2, leads to increased energy expenditure in skeletal muscle and brown adipocytes. [14]. Activation of TGR5 in phagocytic cells of the immune system may result in differentially specific translation of the C/EBPb isoform via the AKT-mTOR signaling pathway. This may alter the function of adipose tissue macrophages and enhance insulin action, potentially addressing T2DM. Thus, insulin resistance may be indirectly prevented and T2DM therapy may b e tailored through activation of the TGR5 receptor in macrophages [15]. Another potential connection between TGR5 signaling and enhanced energy expenditure via alterations in the gut microbiome has been proposed [16].The function of activated TGR5 receptor in T2DM is not dependent on GLP-1 alone. TGR5 provides protection against renal failure in obesity and diabetes by influencing mitochondrial growth and division, i.e. biogenesis, and inhibiting renal oxidative stress and lipid accumulation [17]. The increasing significance of TGR5 in obesity has also been noted [14, 18].
Furthermore, CDCA impacts glucose metabolism through the FXR and TGR5 pathways. FXR activation enhances insulin sensitivity and reduces hepatic gluconeogenesis. Activation of TGR5 in the intestine by CDCA stimulates GLP-1 secretion, resulting in increased insulin release and decreased blood glucose levels.These collective effects indicate that CDCA may be a potential treatment option for type 2 diabetes and metabolic syndrome [19].
2.3 Effect of the CDCA in lipid and cholesterol metabolism under the action of LXR
The liver X receptor (LXR) is a nuclear receptor (NR) that regulates lipid metabolism and plays a critical role in maintaining cholesterol levels and maintaining immunity. There are two isoforms of LXR, LXRa and LXRp. LXRa is primarily found in the liver, adipose tissue, and macrophages, while LXRp is found throughout the body. When LXR isoforms are activated by cholesterol-derived oxysterols, they regulate the expression of genes responsible for the transport and metabolism of this cholesterol.
CDCA primarily acts as a messenger for FXR and then indirectly on LXR. Regulation of bile acid balance and lipid metabolism occurs through LXR-related pathways. LXRs help remove cholesterol from cells by increasing the expression of ATP-binding cassette transporters such as ABCA1 and ABCG1, which are required for the formation of high-density lipoprotein (HDL) [20]. Cross-talk between FXR and LXR is important for lipid and glucose metabolism, as well as inflammatory responses.
2.4 FGF19 and CDCA
One important pathway for regulating bile acid synthesis is the gut-liver signaling pathway. The main regulator of this process is the hormone fibroblast growth factor 19 (FGF19). FGF19 is primarily produced in the lower small intestine in response to increased bile salts, typically after meals. [21]. When CDCA binds to FXR, the FGF19 gene is activated, resulting in the release of FGF19 into the portal circulation. Then, acting as an endocrine factor, FGF19 binds to the dual FGF receptor 4 (FGFR4)/Klotho-p receptor on hepatocytes. Activated FGFR4 receptor affects CYP7A1 gene silencing through interaction between c-Jun (transcription factor) and transcriptional coactivator PGC-1a. Another mechanism involves activation of extracellular signal-regulated kinase (ERK), which leads to stabilization of SHP protein by preventing its degradation [22]. Increasing the concentration of FGF19 reduces the synthesis of bile salts, thereby providing a protective effect for the liver. However, a possible disadvantage of FGF19 may be its putative oncogenicity [23]. Long-term exposure to high concentrations of FGF19 may increase the risk of developing cancer of the bile ducts, gallbladder, and colon in patients with primary sclerosing cholangitis (PSC) [24].
Scientists are studying whether CDCA, an FXR messenger, is able to regulate the level of synthesis and secretion of FGF19 during cholecystectomy [25]. An equally important process is the conversion of primary bile acids into secondary ones with the participation of intestinal bacteria. Complex mechanisms of interaction between microbiota and bile acids can affect protective immune responses, as well as negatively contribute to the development of hepatobiliary diseases [26].
In summary, the interaction between FGF19 and CDCA is essential for controlling bile acid metabolism, impacting glucose and lipid metabolism, and is significant for the treatment of metabolic and liver diseases. This highlights the importance of understanding bile acid signaling pathways to develop effective therapies for these conditions. Ongoing research is dedicated to further exploring these interactions to develop successful treatments.
3 CDCA in disease modulation
3.1 Non-Alcoholic Fatty Liver (NAFLD) and Cardiovascular Diseases
Accumulating data from extensive studies indicate the potential of CDCA and its analogs in the treatment of NAFLD. CDCA's association with FXR receptor activation may reduce liver fat accumulation and inflammation, slowing
the progression of NAFLD. New and emerging studies indicate improved liver function and reduced fibrosis in patients with NAFLD, using CDCA doses [27].
A study involving 12 healthy women who received treatment with chenodeoxycholic acid (CDCA) for 2 days demonstrated notable increases in brown fat energy expenditure. Additionally, in vitro--cultured human brown fat cells exposed to CDCA exhibited elevated levels of uncoupling protein 1 (UCP1) expression [28, 29].
A diagnostic signal in patients with NAFLD is decreased FXR expression mediated by increased levels of the liver sterol regulatory element binding protein-1c (SREBP-1c) receptor LXR [30]. Bile acids activate hepatic FXR and promote the expression of SHP, which then inhibits SREBP-1c and reduces fatty acid synthesis [31]. FXR also suppresses the expression of the ApoB gene, which leads to decreased secretion of very low density lipoprotein (VLDL) [32].
CDCA and similar compounds have demonstrated promise in the treatment of cardiovascular diseases by enhancing lipid profiles and decreasing inflammation. Cardiometabolic diseases are linked to glucose and lipid metabolism, inflammatory response, and mitochondrial function. Activation of FXR by CDCA can lower triglycerides and raise HDL cholesterol levels, which is advantageous for heart health. Furthermore, the anti-inflammatory properties of FXR activation may decrease vascular inflammation, potentially reducing the likelihood of atherosclerosis and other cardiovascular conditions.
3.2 Type 2 Diabetes Mellitus (T2DM)
A new perspective on the study of glucoregulation and insulin resistance focuses on the use of CDCA as an activator of the FXR and TGR5 receptors. Studies using whole-body FXR knockout mice have shown decreased insulin sensitivity, but treatment with the FXR agonist GW4064 was found to significantly enhance insulin resistance and glucose regulation in ob/ob mice with genetic leptin deficiency [33]. FXR activation reduces hepatic gluconeogenesis by reducing the expression of critical enzymes such as G6Pase and PEPCK, which are vital for maintaining glucose levels [34]. Activation of TGR5 stimulates the secretion of GLP-1, which in turn leads to the release of insulin. Attempts to reduce insulin levels have been demonstrated in clinical trials with FXR agonists. For example, FXR agonists can reduce fasting glucose levels and improve glycemic control in patients with type 2 diabetes, indicating the potential of CDCA-based therapy in the treatment of diabetes. This mechanism not only protects pancreatic P-cells from apoptosis, but also promotes their proliferation [35]. More and more, researchers are indicating that TGR5, found in a- and P-cells of the pancreas, plays a role in stimulating insulin secretion and maintaining gluconeogenesis [36]. Stabilization of gluconeogenesis occurs in both adipose and muscle tissues with activation of LXR, which leads to increased GLUT4 expression [37]. Bile acids also interact with FXR in ileal enterocytes, stimulating FGF15/19 signaling, which helps improve glucose regulation [38].
3.3 Role of CDCA in Cerebrotendinous xanthomatosis (CTX)
Cerebrotendinous xanthomatosis (CTX) is a rare disorder characterized by a bile acid synthesis disorder inherited in an autosomal recessive manner. In 2017, CDCA received orphan drug status for the treatment of patients with CTX. Cerebrotendinous xanthomatosis is caused by mutations in the sterol 27-hydroxylase gene (CYP27A1), which leads to lipid accumulation and subsequently to elevated levels of cholestanol in the blood and tissues. Patients have very low or absent CDCA production. In these cases, CDCA is a strong inhibitor of CYP27A1, and the standard treatment for CTX is early CDCA therapy at doses up to 750 mg/day. This treatment leads to a decrease in blood cholestanol levels and stabilization of neurological symptoms. Studies in patients with CTX have also shown that CDCA can inhibit HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase activity in the liver. Additionally, CDCA has been found to stimulate GLP-1 release in patients with diabetes, possibly through activation of GPBAR1 [39]. Studies are currently underway to examine the use of CDCA in pregnant women with cerebrotendinous xanthomatosis [40].
3.4 Interaction CDCA with the gut microbiome
The composition and function of the gut microbiome are significantly affected by CDCA. CDCA alters the abundance of certain bacterial taxa that participate in bile acid metabolism, ultimately influencing the enterohepatic circulation of bile acids. The intestine is an immunological organ, so maintaining gut health and preventing metabolic disorders such as inflammatory bowel disease (IBD) and NAFLD depend on these interactions. Potent natural activators of TGR5 are lithocholic acid (LCA) and deoxycholic acid (DCA), which are secondary bile acids formed metabolically from chenodeoxycholic acid (CDCA) and cholic acid (CA), respectively. Intestinal bacteria mainly regulate this transformation, namely Clostridium spp. (e.g. Cl. scindens and Cl. sordellii), Bacteroides spp. (e.g., B. fragilis) and Eubacterium spp. (e.g., E. lentum). CDCA-induced changes in gut microbiota may also impact overall inflammation and metabolic health [41]. Microbiological studies have shown that obeticholic acid (OCA), a CDCA analog, suppresses the production of natural bile acids and leads to an increase in the proportion of Firmicutes spp. in the small intestine [42, 43]. Moreover, patients with gallstone disease with dysbiotic intestinal disorders showed an increase in the phylum Firmicutes after UDCA/CDCA treatment. High levels of the phylum Firmicutes may also indicate a lack of a beneficial response to UDCA/CDCA treatment. In recent years, extensive research has been conducted on the phylum Firmicutes, a major group of bacteria in the human gut microbiome. The role of Firmicutes spp. in human health is complex and not fully understood; however, it has been associated with a number of health consequences, both beneficial and harmful [44].
Conclusion
In conclusion, Chenodeoxycholic acid (CDCA) is a key signaling molecule that plays a significant role in metabolic processes, immune responses, and inflammation through interactions with receptors such as FXR and TGR5. Its ability to regulate lipid and glucose metabolism, as well as gene expression, makes it a promising treatment option for conditions like non-alcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (T2DM), and cardiovascular diseases.
The potential of CDCA to reduce hepatic fat accumulation, enhance insulin sensitivity, and improve lipid profiles highlights its therapeutic value. Its anti-inflammatory properties and impact on glucagon-like peptide-1 (GLP-1) secretion further underscore its benefits. However, the complex interactions of CDCA with FXR and LXR must be carefully managed to prevent potential side effects, particularly on lipid profiles that could increase cardiovascular risks.
Further research is needed to fully understand the molecular mechanisms of CDCA, establish optimal therapeutic dosages, and assess long-term effects. With more knowledge, CDCA could play a crucial role in developing innovative treatments for metabolic and liver diseases, as long as its usage is guided by comprehensive scientific understanding and meticulous clinical management to maximize advantages and minimize risks.
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